Tony Yu-Xiu Lin, Thai-Yen Ling
Department and Graduate Institute of Pharmacology, National Taiwan University, College of Medicine, Taipei, Taiwan

From the earliest stages of life on Earth, organisms have adapted to the predictable cycles of day and night. This evolutionary adaptation has given rise to the circadian rhythm, an intrinsic 24‑hour biological cycle regulating physiological activities across living organisms—from cyanobacteria to humans. Initially studied primarily in the context of sleep, circadian rhythms are now understood to play vital roles in regulating metabolism, immune function, cardiovascular health, and reproductive physiology [1, 2].

Disruption of circadian rhythms has been linked to a range of diseases, including metabolic disorders, cancer, cardiovascular events, and notably, female reproductive failure such as primary ovarian insufficiency (POI) [3]. Recent findings further highlight a bidirectional interaction between ovarian function and systemic circadian regulation—clock genes such as Bmal1, Per2, and Rev‑erbα exhibit rhythmic expression in ovarian tissue and are tightly coupled with hypothalamic rhythmic signals. Disruption of this interplay is now thought to contribute to ovulatory dysfunction and fertility decline, paving the way for novel therapeutic strategies, including estrogen-sensitive mesenchymal stem cell (MSC) therapy.

Circadian Rhythm: A Body-Wide Timekeeper

Circadian rhythms are governed by a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which synchronizes peripheral clocks found in virtually all tissues, including the liver, kidneys, heart, lungs, and ovaries. These peripheral clocks respond not only to cues from the SCN but also to external stimuli like feeding, exercise, and light exposure, maintaining systemic homeostasis [4].

The significance of circadian rhythms in medicine is underscored by studies showing that the timing of drug administration—known as chronotherapy—can significantly alter therapeutic outcomes. For instance, chemotherapy aligned with a patient’s circadian rhythm has demonstrated improved efficacy and reduced toxicity compared to conventional dosing regimens [5].

Disruption of Circadian Rhythms in POI

Primary ovarian insufficiency (POI), affecting approximately 1% of women under age 40, is characterized by the early loss of ovarian follicular function, leading to infertility, amenorrhea, hypoestrogenism, and elevated FSH levels. Chemotherapy is a leading cause of iatrogenic POI, as alkylating agents like cyclophosphamide (CTX) induce DNA damage and apoptosis in granulosa and oocyte cells [6].

Recent evidence reveals that ovarian tissues possess their own peripheral circadian clocks, expressing genes such as Bmal1, Per2, Rev-erbα, and Rora, which exhibit rhythmicity and are modulated by both gonadotropins and estrogen. This bidirectional communication between the SCN and ovaries means that circadian rhythm disruption can exacerbate ovarian dysfunction, and vice versa [7]. For example, Bmal1 knockout mice exhibit implantation failure and infertility, while Per2 deficiency affects estrogen receptor stability. Estrogen itself regulates clock genes through estrogen response elements (EREs) [8], while clock proteins like BMAL1/CLOCK influence the transcription of ERα, forming a tightly regulated feedback loop [9].

MSC Therapy as a Strategy to Restore Ovarian and Circadian Function

Conventional hormone replacement therapy (HRT) for primary ovarian insufficiency (POI) can relieve symptoms, but it often fails to restore fertility and carries long-term risks, including an increased likelihood of hormone-sensitive cancers. In contrast, mesenchymal stem cells (MSCs) have gained attention as a regenerative therapy, thanks to their ability to modulate inflammation, promote blood vessel growth, and support damaged tissue microenvironments. A groundbreaking study by Le et al. (2024) [9] explored this approach using estrogen receptor-positive placenta-derived MSCs (ER⁺pcMSCs). By harnessing the secretome of these cells—including both unprimed conditioned medium (CM) and estradiol-primed CM (E2-CM)—the researchers tested their effects in a cyclophosphamide-induced POI mouse model.

The results were striking. Treatment with CM and E2-CM improved ovarian follicle development and enhanced steroid hormone synthesis, as evidenced by increased expression of enzymes such as CYP19A1 and StAR. Hormonal balance was partially restored, with elevated estradiol (E2), reduced follicle-stimulating hormone (FSH), and increased anti-Müllerian hormone (AMH) levels. At the cellular level, granulosa cell apoptosis was reduced, and angiogenesis was promoted, with angiogenin identified as a critical factor. Most notably, E2-CM treatment reinstated the rhythmic expression of ovarian clock genes—including Per2, Rev-erbα, and Rora—and restored the mice’s disrupted behavioral circadian activity. Further analysis revealed that the exosomal microRNAs contained within the MSC secretome were targeting genes implicated in cell death, fibrosis, and circadian regulation, suggesting a broad and coordinated mechanism of action.

This study is the first to show that stem cell therapy—specifically through the use of an estrogen-sensitive MSC secretome—can simultaneously restore both ovarian function and circadian rhythm, marking a significant advance in the treatment of POI.

The interplay between circadian rhythm and ovarian health offers a compelling new paradigm in reproductive medicine. Disruption of the ovarian circadian clock contributes to follicular atresia and infertility, particularly in chemotherapy-induced POI. Yet, targeting this disruption via the secretome of ER⁺ MSCs presents a novel dual-action therapy: one that regenerates ovarian tissue and recalibrates systemic rhythmicity.

References

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